{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T01:40:06Z","timestamp":1772761206504,"version":"3.50.1"},"reference-count":53,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2020,3,28]],"date-time":"2020-03-28T00:00:00Z","timestamp":1585353600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Pancreatic duct adenocarcinoma (PDAC) is projected to become the second leading cause of cancer-related deaths in the next few years. Unfortunately, the development of novel therapies for PDAC has been challenged by a uniquely complex tumor microenvironment. The development of in vitro cancer organoids in recent years has demonstrated potential to increase therapies for patients with PDAC. Organoids have been established from PDAC murine and human tissues and they are representative of the primary tumor. Further, organoids have been shown beneficial in studies of molecular mechanisms and drug sensitivity testing. This review will cover the use of organoids to study PDAC development, invasiveness, and therapeutic resistance in the context of the tumor microenvironment, which is characterized by a dense desmoplastic reaction, hindered immune activity, and pro-tumor metabolic signaling. We describe investigations utilizing organoids to characterize the tumor microenvironment and also describe their limitations. Overall, organoids have great potential to serve as a versatile model of drug response and may be used to increase available therapies and improve survival for patients with PDAC.<\/jats:p>","DOI":"10.3390\/cancers12040811","type":"journal-article","created":{"date-parts":[[2020,4,1]],"date-time":"2020-04-01T05:52:30Z","timestamp":1585720350000},"page":"811","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["An Organotypic Microcosm for the Pancreatic Tumor Microenvironment"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1250-1254","authenticated-orcid":false,"given":"Miranda","family":"Lin","sequence":"first","affiliation":[{"name":"Department of Surgery, University of Kentucky, Lexington, KY 40536, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mei","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Kentucky, Lexington, KY 40536, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Prakash K.","family":"Pandalai","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Kentucky, Lexington, KY 40536, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael J.","family":"Cavnar","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Kentucky, Lexington, KY 40536, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joseph","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Kentucky, Lexington, KY 40536, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,3,28]]},"reference":[{"key":"ref_1","unstructured":"Howlander, N., Noone, A.M., Krapcho, M., Miller, D., Brest, A., Yu, M., Ruhl, J., Tatalovich, Z., Mariotto, A., and Lewis, D.R. (2020, February 18). SEER Cancer Statistics Review, 1975\u20132016, Available online: https:\/\/seer.cancer.gov\/csr\/1975_2016\/."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2913","DOI":"10.1158\/0008-5472.CAN-14-0155","article-title":"Projecting cancer incidence and deaths to 2030: The unexpected burden of thyroid, liver, and pancreas cancers in the United States","volume":"74","author":"Rahib","year":"2014","journal-title":"Cancer Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1016\/j.pharmthera.2017.05.012","article-title":"Emerging roles of the CXCL12\/CXCR4 axis in pancreatic cancer progression and therapy","volume":"179","author":"Sleightholm","year":"2017","journal-title":"Pharmacol. Ther."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e119421","DOI":"10.1016\/j.biomaterials.2019.119421","article-title":"Modulation of redox metabolism negates cancer-associated fibroblasts-induced treatment resistance in a heterotypic 3D culture platform of pancreatic cancer","volume":"222","author":"Broekgaarden","year":"2019","journal-title":"Biomaterials"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Upadhrasta, S., and Zheng, L. (2019). Strategies in developing immunotherapy for pancreatic cancer: Recognizing and correcting multiple immune \u201cdefects\u201d in the tumor microenvironment. J. Clin. Med., 8.","DOI":"10.3390\/jcm8091472"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1038\/s41416-018-0298-0","article-title":"Direct therapeutic targeting of immune checkpoint PD-1 in pancreatic cancer","volume":"120","author":"Gao","year":"2019","journal-title":"Br. J. Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1016\/j.cell.2014.12.021","article-title":"Organoid models of human and mouse ductal pancreatic cancer","volume":"160","author":"Boj","year":"2015","journal-title":"Cell"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1474","DOI":"10.1016\/j.gie.2017.12.032","article-title":"Successful creation of pancreatic cancer organoids by means of EUS-guided fine-needle biopsy sampling for personalized cancer treatment","volume":"87","author":"Tiriac","year":"2018","journal-title":"Gastrointest. Endosc."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"952","DOI":"10.1126\/science.aaw6985","article-title":"Cancer modeling meets human organoid technology","volume":"364","author":"Tuveson","year":"2019","journal-title":"Science"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e9301382","DOI":"10.1155\/2019\/9301382","article-title":"Pancreatic progenitors and organoids as a prerequisite to model pancreatic diseases and cancer","volume":"2019","author":"Hohwieler","year":"2019","journal-title":"Stem Cells Int."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"998","DOI":"10.1158\/2159-8290.CD-14-0001","article-title":"Patient-derived xenograft models: An emerging platform for translational cancer research","volume":"4","author":"Hidalgo","year":"2014","journal-title":"Cancer Discov."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Tsai, S., McOlash, L., Palen, K., Johnson, B., Duris, C., Yang, Q., Dwinell, M.B., Hunt, B., Evans, D.B., and Gershan, J. (2018). Development of primary human pancreatic cancer organoids, matched stromal and immune cells and 3D tumor microenvironment models. BMC Cancer, 18.","DOI":"10.1186\/s12885-018-4238-4"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1158\/1541-7786.MCR-18-0531","article-title":"Human organoids share structural and genetic features with primary pancreatic adenocarcinoma tumors","volume":"17","author":"Weber","year":"2019","journal-title":"Mol. Cancer Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1994","DOI":"10.1002\/ijc.31592","article-title":"KRAS mutation and epithelial-macrophage interplay in pancreatic neoplastic transformation","volume":"143","author":"Bishehsari","year":"2018","journal-title":"Int. J. Cancer"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Waters, A.M., and Der, C.J. (2018). KRAS: The critical driver and therapeutic target for pancreatic cancer. Cold Spring Harb. Perspect. Med., 8.","DOI":"10.1101\/cshperspect.a031435"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e6744","DOI":"10.1038\/ncomms7744","article-title":"Whole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets","volume":"6","author":"Witkiewicz","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Gendoo, D.M.A., Denroche, R.E., Zhang, A., Radulovich, N., Jang, G.H., Lemire, M., Fischer, S., Chadwick, D., Lungu, I.M., and Ibrahimov, E. (2019). Whole genomes define concordance of matched primary, xenograft, and organoid models of pancreas cancer. PLoS Comput. Biol., 15.","DOI":"10.1371\/journal.pcbi.1006596"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1112","DOI":"10.1158\/2159-8290.CD-18-0349","article-title":"Organoid profiling identifies common responders to chemotherapy in pancreatic cancer","volume":"8","author":"Tiriac","year":"2018","journal-title":"Cancer Discov."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Coetzee, A., Grose, R., and Kocher, H. (2019). Pancreatic cancer organotypic models. Curr. Top. Microbiol. Immunol.","DOI":"10.1007\/82_2019_155"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1156","DOI":"10.1126\/science.aaw3145","article-title":"The glycan CA19-9 promotes pancreatitis and pancreatic cancer in mice","volume":"364","author":"Engle","year":"2019","journal-title":"Science"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1016\/j.ccr.2012.07.024","article-title":"EGF receptor is required for KRAS-induced pancreatic tumorigenesis","volume":"22","author":"Ardito","year":"2012","journal-title":"Cancer Cell"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.jcmgh.2019.09.001","article-title":"Loss of pancreatic E-cadherin causes pancreatitis-like changes and contributes to carcinogenesis","volume":"9","author":"Kaneta","year":"2020","journal-title":"Cell. Mol. Gastroenterol. Hepatol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"7573","DOI":"10.1021\/acs.nanolett.9b00859","article-title":"Impacting pancreatic cancer therapy in heterotypic in vitro organoids and in vivo tumors with specificity-tuned, NIR-activable photoimmunonanoconjugates: Towards conquering desmoplasia?","volume":"19","author":"Obaid","year":"2019","journal-title":"Nano Lett."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1","DOI":"10.18632\/genesandcancer.184","article-title":"Utilizing cell line-derived organoids to evaluate the efficacy of a novel LIFR-inhibitor, EC359 in targeting pancreatic tumor stroma","volume":"10","author":"Hall","year":"2019","journal-title":"Genes Cancer"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1177\/2472555218766842","article-title":"Advanced development of primary pancreatic organoid tumor models for high-throughput phenotypic drug screening","volume":"23","author":"Hou","year":"2018","journal-title":"SLAS Discov."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.canlet.2018.03.031","article-title":"Basement membrane destruction by pancreatic stellate cells leads to local invasion in pancreatic ductal adenocarcinoma","volume":"425","author":"Koikawa","year":"2018","journal-title":"Cancer Lett."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.stem.2015.02.015","article-title":"The cancer stem cell niche: How essential is the niche in regulating stemness of tumor cells?","volume":"16","author":"Plaks","year":"2015","journal-title":"Cell Stem Cell"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"E2357","DOI":"10.1073\/pnas.1701219114","article-title":"Genetic dissection of colorectal cancer progression by orthotopic transplantation of engineered cancer organoids","volume":"114","author":"Fumagalli","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"856","DOI":"10.1016\/j.cell.2018.07.027","article-title":"Divergent routes toward Wnt and R-spondin niche independency during human gastric carcinogenesis","volume":"174","author":"Nanki","year":"2018","journal-title":"Cell"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1016\/j.stem.2017.12.009","article-title":"Human pancreatic tumor organoids reveal loss of stem cell niche factor dependence during disease progression","volume":"22","author":"Seino","year":"2018","journal-title":"Cell Stem Cell"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1671","DOI":"10.1038\/sj.bjc.6605968","article-title":"CXCL12-CXCR4 signalling axis confers gemcitabine resistance to pancreatic cancer cells: A novel target for therapy","volume":"103","author":"Singh","year":"2010","journal-title":"Br. J. Cancer"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1097\/MPA.0000000000000543","article-title":"Optical imaging of drug-induced metabolism changes in murine and human pancreatic cancer organoids reveals heterogeneous drug response","volume":"45","author":"Walsh","year":"2016","journal-title":"Pancreas"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1158\/1541-7786.MCR-16-0260","article-title":"ECM composition and rheology regulate growth, motility, and response to photodynamic therapy in 3D models of pancreatic ductal adenocarcinoma","volume":"15","author":"Cramer","year":"2017","journal-title":"Mol. Cancer Res."},{"key":"ref_34","first-page":"565","article-title":"Coexpression of epidermal growth factor receptor and ligands in human pancreatic cancer is associated with enhanced tumor aggressiveness","volume":"13","author":"Yamanaka","year":"1993","journal-title":"Anticancer Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"L1025","DOI":"10.1152\/ajplung.00526.2018","article-title":"Epidermal growth factor receptor paracrine upregulation in idiopathic pulmonary fibrosis fibroblasts is blocked by nintedanib","volume":"316","author":"Brook","year":"2019","journal-title":"Am. J. Physiol. Lung Cell Mol. Physiol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"LeBleu, V.S., and Kalluri, R. (2018). A peek into cancer-associated fibroblasts: Origins, functions and translational impact. Dis. Models Mech., 11.","DOI":"10.1242\/dmm.029447"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1016\/j.cell.2016.06.056","article-title":"NRF2 promotes tumor maintenance by modulating mRNA translation in pancreatic cancer","volume":"166","author":"Chio","year":"2016","journal-title":"Cell"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2482","DOI":"10.1158\/1078-0432.CCR-17-3070","article-title":"Oxidative phosphorylation as an emerging target in cancer therapy","volume":"24","author":"Ashton","year":"2018","journal-title":"Clin. Cancer Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e114790","DOI":"10.1016\/j.taap.2019.114790","article-title":"Development of organoid-based drug metabolism model","volume":"385","author":"Park","year":"2019","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"6164","DOI":"10.1158\/0008-5472.CAN-13-0527","article-title":"Optical metabolic imaging identifies glycolytic levels, subtypes, and early-treatment response in breast cancer","volume":"73","author":"Walsh","year":"2013","journal-title":"Cancer Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2455","DOI":"10.1056\/NEJMoa1200694","article-title":"Safety and activity of anti-PD-L1 antibody in patients with advanced cancer","volume":"366","author":"Brahmer","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"828","DOI":"10.1097\/CJI.0b013e3181eec14c","article-title":"Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma","volume":"33","author":"Royal","year":"2010","journal-title":"J. Immunother."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1158\/2326-6066.CIR-14-0027","article-title":"Immunotherapy converts nonimmunogenic pancreatic tumors into immunogenic foci of immune regulation","volume":"2","author":"Lutz","year":"2014","journal-title":"Cancer Immunol. Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"734","DOI":"10.2174\/156800911796191024","article-title":"Myeloid-derived suppressor cells: General characteristics and relevance to clinical management of pancreatic cancer","volume":"11","author":"Goedegebuure","year":"2011","journal-title":"Curr. Cancer Drug Targets"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1056\/NEJMoa1003466","article-title":"Improved survival with ipilimumab in patients with metastatic melanoma","volume":"363","author":"Hodi","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1540","DOI":"10.1016\/S0140-6736(15)01281-7","article-title":"Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): A randomised controlled trial","volume":"387","author":"Herbst","year":"2016","journal-title":"Lancet"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1710","DOI":"10.1021\/acsbiomaterials.6b00246","article-title":"Bioprinting the Cancer Microenvironment","volume":"2","author":"Zhang","year":"2016","journal-title":"ACS Biomater. Sci. Eng."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.trecan.2015.12.003","article-title":"Microfluidics: A new tool for modeling cancer-immune interactions","volume":"2","author":"Li","year":"2016","journal-title":"Trends Cancer"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/j.biomaterials.2017.04.017","article-title":"Advanced biomaterials and bioengineering technologies to recapitulate the stepwise process of cancer metastasis","volume":"133","author":"Peela","year":"2017","journal-title":"Biomaterials"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Hakobyan, D., Medina, C., Dusserre, N., Stachowicz, M.L., Handschin, C., Fricain, J.C., Guillermet-Guibert, J., and Oliveira, H. (2020). Laser-assisted 3D bioprinting of exocrine pancreas spheroid models for cancer initiation study. Biofabrication.","DOI":"10.1088\/1758-5090\/ab7cb8"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1038\/nbt.2958","article-title":"3D bioprinting of tissues and organs","volume":"32","author":"Murphy","year":"2014","journal-title":"Nat. BIotechnol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"e4","DOI":"10.1186\/s13046-017-0654-6","article-title":"Microfluidic co-culture of pancreatic tumor spheroids with stellate cells as a novel 3D model for investigation of stroma-mediated cell motility and drug resistance","volume":"37","author":"Lee","year":"2018","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"e22","DOI":"10.1186\/s40164-017-0084-3","article-title":"Microfluidic device for primary tumor spheroid isolation","volume":"6","author":"Zhou","year":"2017","journal-title":"Exp. Hematol. Oncol."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/12\/4\/811\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:12:42Z","timestamp":1760173962000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/12\/4\/811"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,3,28]]},"references-count":53,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2020,4]]}},"alternative-id":["cancers12040811"],"URL":"https:\/\/doi.org\/10.3390\/cancers12040811","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,3,28]]}}}